The 57 KD serine/threonine kinase, Akt, plays an important role in the regulation of cell survival. Also known as protein kinase B (PKB), Akt is involved in promoting the proliferation and survival of a wide range of cell types, thereby protecting cells from apoptosis. Three members of the Akt subfamily have been identified: Akt1, Akt, and Akt3, which exhibit an overall homology of 80% (Staal, S. P. (1987) Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys. Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem. 2:939-971; WO 2005/113762). Akt activity is regulated by various protein kinases and phosphatases. Akt is downstream of phosphatidylinositol 3-kinase (PI3K) in the signal transduction pathway (Hemmings, B. A. (1997) Science 275:628; Hay N. (2005) Cancer Cell 8:179-183). For instance, activation of Akt is mediated by PI3K which initiates the binding of second messenger phospholipids (e.g. phosphatidyl-inositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate) to the pleckstrin homology (PH) binding domain of Akt, thereby resulting in phosphorylation and activation of the enzyme. An overview of the signaling pathway involving Akt is discussed in Steelman, et al. “Roles of Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging.” Aging, March 2011, Vol. 3, No. 3, 192-222.
Akt is believed to contribute to cancerous disease states by inhibiting apoptosis and promoting both angiogenesis and proliferation (Toker et al (2006) Cancer Res. 66(8):3963-3966). Overexpression or amplification of Akt has been associated with certain cancers. For example, Akt2 is overexpressed in ovarian cancer (Cheng et al (1992) Proc. Natl. Acad. Sci. USA 89:9267); pancreatic cancer (Cheng et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641; Bellacosa et al (1995) Int. J. Cancer 64:280-285); and head and neck cancer (Calhoub N. et al. (2009) Ann. Rev. Pathol. Mech Dis. 4:127-150). Similarly, Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol. Chem. 274:21528-21532 (1999). Akt has also been found to be overexpressed in, for example, colon cancer (Zinda et al (2001) Clin. Cancer Res. 7:2475), brain cancer (Haas Kogan et al (1998) Curr. Biol. 8:1195), lung cancer (Brognard et al (2001) Cancer Res. 61:3986), prostate cancer (Graff et al (2000) J. Biol. Chem. 275:24500) and gastric carcinomas (Staal et al (1987) Proc. Natl. Acad. Sci. USA 84:5034-5037). Dysregulation of the Akt pathway has also been associated with melanoma (Karst A. M., et al. (2006) 66:9221-9226). Activation of Akt has also been implicated as a risk factor for hepatocellular carcinoma (HCC) (Steelman, et al. Aging, March 2011, Vol. 3, No. 3, 192-222).
Because of its contributing role in the regulation of cell survival, Akt provides an important therapeutic target for the effective treatment of various disorders, particularly cancer. Thus, new or improved agents which inhibit kinases such as Akt are continually needed for developing new and more effective pharmaceuticals that are aimed at treating diseases associated with dysregulation of the pathways involving Akt. The compounds, compositions, and methods of the invention described herein are directed toward these needs and other ends.